Glial cell-line derived neurotrophic factor (GDNF) has neuroprotective (NP) and reparative (NR) effects on the dopaminergic (DAergic) nigrostriatal (NS) system in 6-OHDA and MPTP animal models of Parkinson's disease (PD). An understanding of the mechanisms whereby GDNF exerts its effects may lead to the utilization of GDNF in the treatment of PD. MPTP and 6-OHDA impair mitochondrial respiratory chain (MRC) function and produce conditions of oxidative stress. Oxygen radical scavenging (ORS) enzymes have been reported to be increased in some systems treated with other growth factors; therefore, we hypothesize that GDNF may exert its NP/NR effects through changes in ORS and/or MRC enzymes. We plan to study the effects of GDNF before and after administration of 6-OHDA in rats and MPTP in mice. Control groups will include; 1) GDNF-non-neurotoxin; 2) neurotoxin- nonGDNF; and 3) non-neurotoxin-nonGDNF (i.e., vehicle) treated animals. Assessment of DAergic system function will determine which components of DAergic function contribute to the effects of GDNF and will provide control data for the proposed investigations. These studies will include; 1) catecholamine (CA) synthesis [tyrosine hydroxylase (TH) activity and protein levels; TH cofactor tetrahydrobiopterin (BH4) level and activity of cofactor- synthesizing enzyme GTP-cyclohydrolase]; 2) CA and metabolite levels; 3) CA metabolizing enzyme monoamine oxidase-A and -B activities; 4) DA uptake including determination of number of mazindol binding sites; 5) DA D1 and D2 receptor function; and 6) DA neuron responsiveness to haloperidol and electroconvulsive shock treatment. Assessment of GDNF effects on IRS and MRC enzymes will test our hypothesis that GDNF also alters these systems.